ABSTRACT Methamphetamine (meth) use disorder poses unique challenges for treatment due to the prevalence of meth- induced neurocognitive deficits. These deficits contribute to persistent relapse vulnerability and complicate recovery for meth users. Here we utilize a rodent model of extended access to self-administered (SA) meth that captures many symptoms observed in meth users, such as escalation of meth intake, higher propensity to relapse, cognitive inflexibility and deficits in episodic-like memory. Thus, this model is highly suitable for investigation of neurobiology underlying persistent meth-induced deficits and for the screening of potential novel therapeutics. Using this model, we have reported that SA meth reduces cell surface (but not total) expression of metabotropic glutamate receptors (mGlu) 2/3 in the prefrontal cortex (PFC) that persist for up to 30 days of abstinence. This finding is highly relevant for meth use disorder as: a) normal function of mGlu2/3 in the PFC is necessary for optimal cognitive performance, b) increased neuronal activity and enhanced glutamate release in the PFC observed during meth-seeking could be attributed to reduced control of mGlu2/3 over glutamatergic neurotransmission, and c) systemic and intra-PFC activation of mGlu2/3 consistently reduces drug-seeking. However, these studies did not molecularly or pharmacologically separate mGlu2 from 3, and significant differences in signaling and behavioral output occur when each receptor alone is targeted. Furthermore, no pharmacological tools exists that would reverse the loss of mGlu2 (or 3) receptor function. The present proposal is significant because it will be the first to evaluate the surface expression of mGlu2 vs. 3 separately after meth SA, or otherwise. It will also be the first to consider sex-differences as a factor in such expression. This proposal?s innovation stems from the development of novel tools (interference peptides) to increase mGlu2(3) surface availability/function after their in vivo administration. Finally, we aim to develop a highly-translational intranasal route of administration of such peptides. We hypothesize that this approach will allow for selective restoration of mGlu2 and/or 3 surface expression and function in subjects with a history of chronic meth exposure. We will test this hypothesis in the following specific aims: Aim 1- Evaluate sex-differences in surface availability and function of mGlu2 and mGlu3 in the PFC, and Aim 2- Develop and optimize the in vivo delivery of interference peptides that reverse post-meth changes in mGlu2 (or 3) surface expression and function in the PFC. To achieve these ambitious aims, we propose to develop innovative tools ? receptor-specific interference peptides. Evidence- based prediction is that these peptides will normalize the surface expression/function of mGlu2(3) without the potential side-effects produced by traditional receptor ligands. In summary, the proposed experiments will evaluate the utility of cortical mGlu2(3) receptors as a target for development of novel, neurobiologically-based treatments, that can be used to improve cognitive performance and reduce the vulnerability to meth relapse.